Kamada, Ltd.v.Grifols SA

Patent Trial and Appeal Board

Dec 15, 2015

09449695 (P.T.A.B. Dec. 15, 2015)

Trials@uspto.gov Paper 43
571-272-7822 Entered: December 15, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

KAMADA, LTD.,
Petitioner,

v.

GRIFOLS THERAPEUTICS INC.,
Patent Owner.
____________

Case IPR2014-00899
Patent 6,462,180 B1
____________

Before RAMA G. ELLURU, SHERIDAN K. SNEDDEN, and
TINA E. HULSE, Administrative Patent Judges.

HULSE, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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INTRODUCTION I.
Kamada, Ltd. (“Petitioner”) filed a Petition requesting an inter
partes review of claims 1–33 of U.S. Patent No. 6,462,180 B1
(Ex. 1001, “the ’180 patent”). Paper 1 (“Pet.”). Grifols Therapeutics
Inc. (“Patent Owner”) filed a Preliminary Response to the Petition.
Paper 7 (“Prelim. Resp.”). On December 18, 2014, we instituted an
inter partes review of claims 1–5, 10–21, 26–28, 32, and 33 on the
grounds of unpatentability alleged in the Petition. Paper 8 (“Dec.
Inst.”), 24. Patent Owner filed a Response to the Petition. Paper 23
(“PO Resp.”). Petitioner filed a Reply to Patent Owner’s Response.
Paper 31 (“Pet. Reply”).
Patent Owner filed a motion to exclude certain portions of
Petitioner’s Reply, certain exhibits, and certain testimony provided by
Dr. James Travis. Paper 34. Petitioner filed an opposition to Patent
Owner’s motion to exclude. Paper 38. And Patent Owner filed a
reply in support of its motion to exclude. Paper 39.
An oral hearing for this proceeding was held on July 23, 2015,
a transcript of which has been entered in the record. Paper 40 (“Tr.”)
We have jurisdiction under 35 U.S.C. § 6(c). This Final
Written Decision is issued pursuant to 35 U.S.C. § 318(a) and
37 C.F.R. § 42.73.
For the reasons that follow, we determine that Petitioner has
shown by a preponderance of the evidence that claims 1–5, 10–21,
26–28, 32, and 33 of the ’180 patent are unpatentable.
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A. Related Proceedings
Petitioner states that the ’180 patent is the subject of a reissue
proceeding (Reissue Application No. 13/567,678) and an ex parte
reexamination proceeding (Reexamination Control No. 90/013,008).
Pet. 1–2; Paper 6, 2. The proceedings have been merged into a single
proceeding. Pet. 2. Of the claims involved in this inter partes review,
Patent Owner canceled claims 2 and 3, and amended claims 1, 4, and
22–24 during the reissue/reexamination proceeding. Ex. 1037, 6. On
October 27, 2015, the Examiner entered a final office action rejecting
pending claims 1 and 4–35 of the reissue application. Ex. 1037.
Because, as of the time of filing this Final Written Decision, the
reissue/reexamination proceeding is still pending and no certificate
has been issued, we consider all of the claims in this Decision.
B. The ’180 Patent (Ex. 1001)
Alpha-1 proteinase inhibitor (“API”) is a glycoprotein that acts
as an inhibitor of endogenous proteases. Ex. 1001, 1:16–23. API is
used to treat patients with a genetic deficiency of API, which can lead
to chronic lung tissue damage and emphysema. Id. at 1:24–32. The
’180 patent relates to the purification of API from blood plasma or
from plasma fractions, such as Cohn Fraction IV-1.1 Id. at 1:5–9.
According to the Specification, “the present invention provides a
process of purifying [API] from a blood plasma fraction with a higher

1 Cohn-Fraction IV-1 is a partially purified plasma fraction enriched
for API that also contains other proteins, lipids, lipoproteins, and other
substances. Ex. 1010 ¶ 8.
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yield, higher purity, shorter production time, and use of less resources
than known methods.” Id. at 2:54–58.
C. Illustrative Claim
Of challenged claims 1–33, claims 1 and 17 are
independent claims. Claim 1 is illustrative of the challenged
claims and is reproduced below:
1. A method of purifying α-1 proteinase inhibitor from an
aqueous solution containing α-1 proteinase inhibitor
comprising:
(a) removing a portion of contaminating proteins from
the aqueous solution by precipitation in order to obtain a
purified solution containing α-1 proteinase inhibitor; then
(b) passing said purified solution through an anion
exchange resin so that α-1 proteinase inhibitor binds to
said anion exchange resin; then
(c) eluting α-1 proteinase inhibitor from said anion
exchange resin to obtain an eluted solution containing α-
1 proteinase inhibitor; then
(d) passing the eluted solution through a cation exchange
resin; then
(e) collecting a flow-through from said cation exchange
resin that contains α-1 proteinase inhibitor.

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D. Grounds of Unpatentability Instituted for Trial
We instituted trial based on the following grounds of
unpatentability:
Claim(s) Basis References
1, 2, 5, 10, 11, 16–18, 21, 26,
27, 32, and 33
§ 102(e) Ralston2
3, 4, 19, and 20 § 103 Ralston and Coan3
12 and 28 § 103 Ralston and Hwang4
13 § 103 Ralston, Hwang, and
Chen5
14 and 15 § 103 Ralston, Hwang, Chen,
and Coan II6
2–5, 12, 16, 18–21, 28, and
32
§ 103 Lebing7 and Coan

ANALYSIS II.
A. The Level of Ordinary Skill in the Art
The parties disagree on the level of ordinary skill in the art.
Petitioner asserts that a skilled artisan would have had at least a
Master’s Degree in Chemistry or Biochemistry, with five or more
years of experience with large-scale protein purification. Pet. 5.

2 Ralston et al., US 6,093,804, issued July 25, 2000 (Ex. 1002).
3 Coan et al., US 4,379,087, issued Apr. 5, 1983 (Ex. 1004).
4 Hwang et al., US 5,616,693, issued Apr. 1, 1997 (Ex. 1005).
5 Chen et al., Purification of α1 Proteinase Inhibitor from Human
Plasma Fraction IV-1 by Ion Exchange Chromatography, 74 VOX
SANG. 232–41 (1998) (Ex. 1007).
6 Michael H. Coan, Purification of Alpha-1-Proteinase Inhibitor, 84
AM. J. MED. 32–36 (1988) (Ex. 1008).
7 Lebing et al., US 5,610,285, issued Mar. 11, 1997 (Ex. 1003).
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Patent Owner argues that a skilled artisan would have had an
advanced degree in biochemistry or a related discipline, and would
have had at least several years of experience in development, testing,
and implementing commercial-scale protein purification methods
from human plasma. PO Resp. 16.
As an initial matter, we note that the claims do not require
large-scale or commercial-scale protein purification. Moreover, not
all claims require plasma-derived API. Accordingly, we determine
that a person of ordinary skill in the art would have had at least a
Master’s Degree in chemistry or biochemistry and at least 35 years
of experience in protein purification.8 We also consider the cited prior
art as representative of the level of ordinary skill in the art. See
Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (holding
the absence of specific findings on “level of skill in the art does not
give rise to reversible error ‘where the prior art itself reflects an
appropriate level and a need for testimony is not shown’”) (quoting
Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163
(Fed. Cir. 1985)).

8 Patent Owner alleges that Petitioner’s declarants are not qualified to
opine on the merits of this proceeding because they have no
experience with plasma-derived protein purification. PO Resp. 16–
24. In light of our decision that a person of ordinary skill in the art
does not require plasma-protein purification experience, we are not
persuaded that Petitioner’s declarants are not qualified, and will
accord their testimony appropriate weight.
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B. Claim Construction
In an inter partes review, the Board interprets claim terms in an
unexpired patent according to the broadest reasonable construction in
light of the specification of the patent in which they appear. See In re
Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1278–79 (Fed. Cir. 2015);
37 C.F.R. § 42.100(b). Under that standard, and absent any special
definitions, we give claim terms their ordinary and customary
meaning, as would be understood by one of ordinary skill in the art at
the time of the invention. See In re Translogic Tech., Inc., 504 F.3d
1249, 1257 (Fed. Cir. 2007). Any special definitions for claim terms
must be set forth with reasonable clarity, deliberateness, and
precision. See In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
1. “precipitation” or “precipitating”
Either the terms “precipitation” or “precipitating” appears in
each of the challenged claims. In the Decision to Institute, we
preliminarily construed both terms to mean “a process to separate or
cause to separate from a solution or suspension.” Dec. Inst. 7. This
construction was based, in part, on our review of several dictionary
definitions presented by Petitioner, through its expert Dr. Carl
Scandella. Pet. 4; Ex. 1010 ¶ 15.
Patent Owner argues that our preliminary construction is overly
broad, and that a person of ordinary skill in the art would understand
that the term “precipitation” as used in the ’180 patent refers to “the
process of selectively reducing the solubility of particular proteins in
the solution by adjusting the solution conditions to facilitate protein
aggregation that causes these proteins to fall out of solution or
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‘precipitate.’” PO Resp. 27. As support, Patent Owner relies on the
testimony of its two declarants, Dr. James Travis and Mr. Michael
Fournel. Ex. 2016 ¶¶ 32–43; Ex. 2017 ¶¶ 21–31.
Patent Owner and its declarants argue that proteins generally
become insoluble at their isoelectric point or when the water structure
surrounding the protein is disrupted. PO Resp. 27; Ex. 2016 ¶ 35;
Ex. 2017 ¶ 23. These effects allow proteins to become insoluble and
aggregate. PO Resp. 27; Ex. 2016 ¶ 35; Ex. 2017 ¶ 23. According to
Patent Owner, typical methods for precipitating proteins include
changing the pH, changing the salt concentration, or adding organic
solvents. PO Resp. 27; Ex. 2016 ¶ 35; Ex. 2017 ¶ 23. As intrinsic
support for its proposed construction, Patent Owner asserts that the
Specification discloses removing contaminating proteins with
polyethylene glycol (“PEG”) and by changing the pH of the solution,
which causes the proteins to become insoluble and precipitate. PO
Resp. 28 (citing Ex. 1001, 4:43–65, Example 2).
Patent Owner then argues that the process of precipitating
proteins differs from the use of lipid removal agents (“LRA”), which
are silicates that specifically bind lipids and lipoproteins through
adsorption. PO Resp. 28; see Ex. 2016 ¶ 43 (“LRA is an adsorption
‘capture’ phenomenon and does not alter protein or lipid solubility in
the solution—the lipoprotein/lipid adsorbs to the insoluble silicate
media—and is removed from the solution via the interaction with the
LRA media.”). The captured protein is then removed from the
solution by centrifugation or filtration. Id. at 29; Ex. 2016 ¶ 40; Ex.
2017 ¶ 28. According to Patent Owner, construing “precipitation” to
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encompass an LRA adsorption process would be unreasonably broad
because “precipitation” is limited to “selectively reducing the
solubility of particular proteins in the solution by adjusting the
solution conditions to facilitate protein aggregation that causes these
proteins to fall out of solution.” PO Resp. 30–31.
Petitioner, on the other hand, argues that our preliminary
construction is correct and is supported by the Specification, the
testimony of both parties’ declarants, and contemporaneous dictionary
definitions. Pet. Reply 4–6. Petitioner cites Example 2 of the
Specification, which describes an embodiment of the precipitation
step of the claims. Id. at 5. Example 2 includes the steps of adding
PEG, acetic acid, and Hyflo Supercel® to Cohn Fraction IV-1 to form
a precipitate. Ex. 1001, 6:63–7:6. Hyflo Supercel®, like LRA, is a
silicate that binds lipids and lipoproteins. Pet. Reply 5; Ex. 1024; Ex.
1032, 85:18–86:16. Petitioner argues that because Patent Owner’s
proposed construction would exclude the preferred embodiment’s use
of Hyflo Supercel®, Patent Owner’s construction cannot be correct.
Pet. Reply 5–6 (citing GE Lighting Solutions, LLC v. AgiLight, Inc.,
750 F.3d 1304, 1311 (Fed. Cir. 2014)).
The parties agree that adding PEG and adjusting the pH of a
solution can cause contaminating proteins to precipitate. Pet. Reply 4;
PO Resp. 28. The dispute is whether the broadest reasonable
interpretation of “precipitation” encompasses removal of proteins that
adsorb to lipid removal agents like Hyflo Supercel®. We determine
that it does.
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As an initial matter, we note that Patent Owner’s declarants
offer little to no persuasive evidence in support of their opinions
regarding how a person of ordinary skill in the art would interpret
“precipitation.” See Ex. 2016 ¶¶ 34–36, 40–43 (failing to cite
persuasive evidence in support of opinions); Ex. 2017 ¶¶ 22–24, 27–
28, 30–31 (same). Under our rules, unsupported expert testimony
may be given little to no weight. See 37 C.F.R. § 42.65(a) (stating
opinion testimony that does not disclose underlying facts or data “is
entitled to little or no weight”); Ashland Oil, Inc. v. Delta Resins &
Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985) (finding a lack
of objective support for expert opinion “may render the testimony of
little probative value in a validity determination”).
In any event, starting with the language of the claims, claim 1
recites the step of “removing a portion of contaminating proteins from
the aqueous solution by precipitation.” The language of claim 17 is
similar, but replaces “aqueous solution” with “Cohn Fraction IV-I.”
Thus, the claim language indicates that “precipitation” is a process for
removing contaminating proteins.
Next, we look to the Specification for further guidance. The
Specification does not expressly define “precipitation.” The parties,
however, both cite Example 2 of the Specification as describing the
precipitation step of the claims. Pet. Reply 5; PO Resp. 28. Example
2 “describes one purification step in the process for the removal of
contaminating proteins” from a suspension of Cohn Fraction IV-1
(Ex. 1001, 6:60–62):
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The Cohn Fraction IV-1 dissolved in the Tris buffer
solution, as described above, is again cooled to between
2° and 8° C. To this cooled solution is added NaCl to
0.11 M. To this solution is then added 11.5% PEG MW
3,350 (Carbowax®, Union Carbide, Danbury, Conn.;
suspension weight in kg times 0.115). The pH of the
solution is then adjusted to between 5.10 and 5.35 with
1.0 M glacial acetic acid. To this is added 2.5% of Hyflo
Supercel® (Celite Corporation, Lompoc, Calif.) and the
resulting solution is mixed for 10 min. A precipitate of
contaminating proteins and viruses, including prion
proteins, is formed. The precipitate is filtered through a
filter press assembled with CP90 Cuno filter pads (Cuno,
Meriden, Conn.) at NMT 20 psi. The press is rinsed with
11.5% PEG in a water buffer. The paste obtained by the
filtration is discarded. The filtrate contains the α-1 PI in
PEG. Alternatively, the precipitate may be centrifuged
and then filtered.
Id. at 6:63–7:12 (emphasis added). Petitioner contends that
Example 2 is evidence that an adsorbent material, Hyflo Supercel®, is
used in forming a precipitate. Pet. Reply 1 (citing Ex. 1001,
6:537:12).
Patent Owner and its declarant argue that Hyflo Supercel® is
used as a filter aid, and is not used to bind proteins. Tr. 39:13–21;
Ex. 1032, 84:18–85:8. Although Dr. Travis agreed that the
Specification does not indicate Hyflo Supercel®’s mechanism of
action, he opined that “[i]f you are a protein chemist, you would
assume that’s what it meant.” Ex. 1032, 85:9–14. Without objective
evidence to support Dr. Travis’s testimony, the Specification is, at
best, ambiguous as to the function of the Hyflo Supercel®.
Regardless, even if we agreed with Patent Owner that Example
2 describes conditions meant to render proteins insoluble and that the
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Hyflo Supercel® material was used as a filter aid alone, we do not
limit the interpretation of the terms “precipitation” or “precipitating”
to a single embodiment.
Rather, we are careful not to limit the claims to particular
embodiments appearing in the written description if the claim
language is broader than the embodiment. In re Van Geuns, 988 F.2d
1181, 1184 (Fed. Cir. 1993); see also Johnson Worldwide Assocs.,
Inc. v. Zebco Corp., 175 F.3d 985, 992 (Fed. Cir. 1999) (“[J]ust as the
preferred embodiment itself does not limit claim terms, mere
inferences drawn from the description of an embodiment of the
invention cannot serve to limit claim terms, as they are insufficient to
require a narrower definition of a disputed term.”) (internal citations
omitted).
We further note that Ralston refers to a “precipitate” in relation
to the use of LRA: “LRA may be removed by filter press filtration or
centrifugation. For filter press filtration, . . . Filter Aid 501 FF is
added before the precipitate is collected.” Ex. 1002, 10:53–56
(emphasis added).
Patent Owner acknowledges the use of the word “precipitate” in
Ralston, but characterizes it as “occasional and idiosyncratic” and
concludes that a person of ordinary skill in the art would not interpret
the term “precipitation” so broadly. PO Resp. 42 (“The occasional
and idiosyncratic use of a term such as ‘precipitate’ in the noun form
to refer to any solid removed from a liquid mixture notwithstanding,
one of ordinary skill in the art would not interpret the claim term
‘precipitation’ as recited in the claims of the ’180 patent, to
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encompass use of a lipid removal agent.”). But Patent Owner’s
wholesale (and unsupported) dismissal of the Specification’s and
Ralston’s use of the word “precipitate” is not persuasive. Given the
definition of “precipitate” is “a substance, usually small crystalline
particles, precipitated from a solution” (Ex. 30019 (emphasis added)),
Patent Owner has not explained why we should not interpret
Example 2’s “precipitate” as a substance that was precipitated by the
addition of PEG, acetic acid, and Hyflo Supercel®. Without a
reasoned, well-supported explanation to the contrary, we find that the
Specification supports a broader construction of “precipitation” that
encompasses the use of LRA to remove contaminating proteins by
adsorption.
Finally, our construction is supported by the extrinsic evidence.
As mentioned above, Ralston’s use of the word “precipitate” to refer
to the use of LRA is consistent with our construction. Ex. 1002,
10:53–56. Our construction is also consistent with certain technical
dictionaries, which define “precipitate” as “to separate or cause to
separate from a solution or suspension” (Ex. 1010 ¶ 15) and define
“precipitation” as “the process of depositing a substance from a
solution, by the action of gravity or by a chemical reaction”
(Ex. 3001). These definitions encompass the removal of proteins
from a solution by adsorbing to LRA and filtering or centrifuging the
precipitate. Although we acknowledge that these definitions are

9 ACADEMIC PRESS DICTIONARY OF SCIENCE AND TECHNOLOGY 1712
(1992).
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broader than other definitions of “precipitate” related to forming an
insoluble solid that separates from a solution (see Ex. 1010 ¶ 15), we
are not persuaded that our construction is unreasonably broad in light
of the ambiguous description of Example 2 in the Specification.
Patent Owner argues that Kamada’s Bauer patent distinguishes
lipid adsorption from precipitation and is, therefore, evidence of how
a person skilled in the art would interpret precipitation. PO Resp. 29
(citing Ex. 2009,10 6:27–32). First, we agree with Petitioner that the
patent is less probative of the meaning of the term “precipitation” in
the ’180 patent claims because the earliest effective filing date of the
Bauer patent is almost four years after the filing date of the ’180
patent. See Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir.
2005) (en banc) (“[T]he ordinary and customary meaning of a claim
term is the meaning that the term would have to a person of ordinary
skill in the art in question at the time of the invention, i.e., as of the
effective filing date of the patent application.”) (emphasis added).
Regardless, we note that, unlike the ’180 patent, the Bauer patent
specification distinguishes between removal of LRA and removal of
the precipitate. See Ex. 2009, 6:36–38 (“The pH reduction improves
the precipitation, and the lipid removal agents and the precipitate are
removed from the suspension.”). That is, Bauer does not refer to the
LRA as part of the precipitate, as the ’180 patent does. See Ex. 1001,
6:63–7:6. We are, therefore, not persuaded that Bauer is inconsistent
with our construction of “precipitation” in the ’180 patent.

10 Bauer, US 7,879,800 B2, issued Feb. 1, 2011 (Ex. 2009).
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In light of the evidence in support and the lack of persuasive
evidence to the contrary, we determine that the broadest reasonable
interpretation of “precipitation” or “precipitating” encompasses the
use of LRA (or an equivalent) to remove contaminating proteins from
a solution.11
2. Order of Steps
In our Decision to Institute, we determined that each of the
steps of the claimed methods must occur in the order stated. Dec.
Inst. 7–8. Neither Petitioner nor Patent Owner challenges this
construction. Pet. Reply 12 (“As a preliminary matter, Kamada does
not dispute that the order of steps is relevant to the claimed
methods.”); PO Resp. 31 (“The Board properly determined that the
steps of claims 1 and 17 must be performed in the recited order.”).
Accordingly, because nothing in the full record developed during trial
persuades us to deviate from our prior construction, we adopt the
construction for purposes of this Decision.

11 To the extent this construction differs from the construction set
forth in the Decision to Institute, we modify our construction
accordingly. We need not consider if the construction should be
broader, as whether the construction encompasses the use of LRA is
determinative in this proceeding. See Wellman, Inc. v. Eastman
Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (“[C]laim terms
need only be construed ‘to the extent necessary to resolve the
controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
200 F.3d 795, 803 (Fed. Cir. 1999)).
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C. Principles of Law
To prevail in this inter partes review of the challenged claims,
Petitioner must prove unpatentability by a preponderance of the
evidence. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
To establish anticipation, each limitation in a claim must be
found in a single prior art reference, arranged as recited in the claim.
Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir.
2008). While the limitations must be arranged or combined in the
same way as in the claim, identity of terminology is not required. In
re Gleave, 560 F.3d 1331, 1334 (Fed. Cir. 2009); In re Bond, 910 F.2d
831, 832 (Fed. Cir. 1990). Moreover, a reference anticipates a claim
“if it discloses the claimed invention such that a skilled artisan could
take its teachings in combination with his own knowledge of the
particular art and be in possession of the invention.” In re Graves, 69
F.3d 1147, 1152 (Fed. Cir. 1995). Thus, “it is proper to take into
account not only specific teachings of the reference but also the
inferences which one skilled in the art would reasonably be expected
to draw therefrom.” In re Preda, 401 F.2d 825, 826 (CCPA 1968).
A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
differences between the claimed subject matter and the prior art are
such that the subject matter, as a whole, would have been obvious at
the time the invention was made to a person having ordinary skill in
the art to which said subject matter pertains. KSR Int’l Co. v. Teleflex
Inc., 550 U.S. 398, 406 (2007). The question of obviousness is
resolved on the basis of underlying factual determinations, including:
(1) the scope and content of the prior art; (2) any differences between
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the claimed subject matter and the prior art; (3) the level of skill in the
art; and (4) objective evidence of nonobviousness. Graham v. John
Deere Co., 383 U.S. 1, 17–18 (1966).
“[A] patent composed of several elements is not proved obvious
merely by demonstrating that each of its elements was, independently,
known in the prior art.” KSR, 550 U.S. at 418. “[I]t can be important
to identify a reason that would have prompted a person of ordinary
skill in the relevant field to combine elements in the way the claimed
new invention does.” Id. Moreover, a person of ordinary skill in the
art must have had a reasonable expectation of success of doing so.
PAR Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1193 (Fed.
Cir. 2014).
We analyze the instituted grounds of unpatentability in
accordance with the above-stated principles.
D. Anticipation by Ralston
Petitioner asserts that claims 1, 2, 5, 10, 11, 16–18, 21, 26, 27,
32, and 33 of the ’180 patent are anticipated by Ralston. Pet. 9–13;
Pet. Reply 6–8. Petitioner also relies on the Declaration of Dr. Carl
Scandella. Ex. 1010 ¶¶16–17, App’x I. Patent Owner disagrees with
Petitioner’s assertions (PO Resp. 41–43), relying on the Declarations
of James Travis, Ph.D. (Ex. 2016 ¶¶ 39–43, 56–66) and Michael
Fournel (Ex. 2017 ¶¶ 27–31, 38–49, 65).
1. Ralston (Ex. 1002)
Ralston relates to a process for purifying API from blood
plasma or blood plasma fractions. Ex. 1002, 1:8–11. Ralston’s
method generally involves the removal of lipoproteins from an initial
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protein suspension using a lipid removal agent (“LRA”), followed by
successive separations with anion and cation exchange resins. Id. at
4:59–64. Thus, according to Ralston, “the present invention provides
a means for achieving high yield isolation and purification of active
API from various sources.” Id. at 4:57–59.
2. Analysis
We have reviewed the arguments and evidence presented by
both parties, and we are persuaded that Petitioner has shown by a
preponderance of the evidence that the challenged claims are
anticipated by Ralston.
For example, claim 1 recites a method of purifying API from
an aqueous solution comprising steps (a) through (e). Petitioner
asserts that Ralston discloses precipitation step (a) because Ralston
teaches that LRA adsorbs contaminating proteins, which together
form a precipitate that is removed by filtration or centrifugation.
Pet. 11; Ex. 1002, 10:47–48, 10:53–56; Ex. 1010 ¶ 16, App’x I.
Petitioner also asserts that Ralston teaches passing the purified
solution through an anion exchange resin that binds API (i.e., step
(b)), eluting API from the anion exchange resin (i.e., step (c)), and
passing the eluted solution through a cation exchange resin (i.e., step
(d)). Pet. 11–12; Ex. 1002, 4:53–57; Ex. 1010 ¶ 16, App’x I. Finally,
Petitioner asserts that Ralston discloses collecting a flow-through
from the cation exchange resin that contains API (i.e., step (e)). Pet.
12; Ex. 1002, 5:40–48. We determine that Petitioner has shown by a
preponderance of the evidence that Ralston discloses each limitation
of claim 1.
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Independent claim 17 recites the same steps as claim 1, but
specifies the starting material as Cohn Fraction IV-1. As Petitioner
asserts, Ralston discloses the use of Cohn Fraction IV-1 as the starting
material. Pet. 12; Ex. 1002, 10:32–37; Ex. 1010 ¶ 16, App’x I. We
are persuaded that Ralston discloses every element of claim 17, as
well.
Patent Owner’s sole argument is that Ralston fails to anticipate
the ’180 patent claims because it fails to disclose a precipitation step
before the anion and cation exchange chromatography steps. PO
Resp. 41–42. Patent Owner then reargues its claim construction
position that “precipitation” does not encompass the use of LRA. Id.
For the same reasons stated above, we are not persuaded by
Patent Owner’s argument. We determine that the broadest reasonable
interpretation of “precipitation” includes the use of LRA. Thus,
contrary to Patent Owner’s assertion, Ralston discloses a precipitation
step before the anion and cation exchange chromatography steps. See,
e.g., Ex. 1002, 4:59–64 (“Generally, the method involves the removal
of lipoproteins from an initial protein suspension by use of a lipid
removal agent . . . followed by successive separations with anion and
cation exchange resins with specific eluants.”).
Accordingly, we determine that Petitioner has shown by a
preponderance of the evidence that independent claims 1 and 17 of the
’180 patent are anticipated by Ralston. Regarding dependent claims
2, 5, 10, 11, 16, 18, 21, 26, 27, 32, and 33, we have considered the
parties’ arguments and evidence, and determine that Petitioner has
shown by a preponderance of the evidence that Ralston discloses each
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limitation of those claims as well. See Pet. 12–13; Ex. 1010 ¶¶ 16–17,
App’x I.
E. Obviousness over Ralston and Coan
Petitioner asserts that claims 3, 4, 19, and 20 of the ’180 patent
are unpatentable as obvious over Ralston and Coan. Pet. 15–19; Pet.
Reply 8–10. Petitioner relies on the Declarations of Dr. Scandella and
Dr. Rainer Bischoff. Ex. 1010 ¶¶ 20–24; Ex. 1011 ¶¶ 8, 10, 18, 19.
Patent Owner disagrees with Petitioner’s assertions, relying on the
Declarations of Dr. Travis and Mr. Fournel. PO Resp. 43–46; Ex.
2016 ¶¶ 76, 77, 79; Ex. 2017 ¶¶ 64, 66. We incorporate here our
earlier findings and discussion regarding the disclosure of Ralston.
1. Coan (Ex. 1004)
Coan relates to a method for separating API from blood plasma
or blood plasma fractions. Ex. 1004, 1:7–10. Coan teaches adding
PEG to blood plasma or a blood plasma fraction and adjusting the pH
of the solution to about 4.6–5.9 “to selectively precipitate unwanted
proteins from the effluent in which a substantial proportion of the
[API] is retained.” Id. at 3:2–4. Coan explains that the “primary
advantage of the present method is that [API] may be separated from
blood plasma in high yield.” Id. at 3:7–8. Moreover, Coan states that
the method “can be carried out inexpensively because of the low cost
of the agents employed in the present method.” Id. at 3:14–16.
2. Analysis
We have reviewed the arguments and evidence presented by
both parties, and we are persuaded that Petitioner has shown by a
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preponderance of the evidence that the challenged claims are
unpatentable as obvious over the combination of Ralston and Coan.
Claims 3 and 19 depend from claims 2 and 18, respectively, and
further recite that the precipitating step comprises the steps of adding
a polyalkylene glycol to the aqueous solution and adjusting the pH of
the aqueous solution to from about 5.0 to about 6.0. Claims 4 and 20
further depend from claims 3 and 19, respectively, and require that the
polyalkylene glycol is PEG.
As explained above, we determine that Ralston discloses each
limitation of claims 2 and 18. For the limitations of dependent claims
3, 4, 19, and 20, Petitioner relies on Coan’s disclosure of adding PEG
and adjusting the pH of the solution to precipitate unwanted proteins.
Pet. 15; Ex. 1010 ¶ 20; Ex. 1011 ¶ 8. We are persuaded that Petitioner
has shown by a preponderance of the evidence that the combination of
Ralston and Coan teaches each limitation of claims 3, 4, 19, and 20.
Petitioner then offers several reasons why a person of ordinary
skill in the art would have had a reason to combine the teachings of
Ralston with Coan. Pet. 15–18; Ex. 1010 ¶¶ 21–24; Ex. 1011 ¶¶ 10,
18, 19. Petitioner’s declarant states that a skilled artisan would have
been motivated to include Coan’s precipitation step in the method of
Ralston because it was well known that contaminating proteins in a
solution of API may interfere with the ion exchange sites on the resin,
thereby making the resin less available for the binding of API. Ex.
1010 ¶ 21. The contaminating materials may also lead to a reduction
in flow rate of a solution through the ion exchange column and foul
the column. Id. According to Dr. Scandella, a person of ordinary
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skill in the art would have expected Coan’s precipitation step to
remove contaminating proteins to allow for increased binding of API
to the anion exchange resin and to decrease the likelihood that the
contaminating proteins would reduce the flow rate of solution through
the column. Id. Petitioner also asserts that a person of ordinary skill
in the art would have expected to increase yield and purity of API per
run by precipitating the contaminating proteins, as disclosed in Coan,
from the solution of Ralston. Pet. 17–18; Ex. 1010 ¶ 22. Finally,
Petitioner asserts that because both references are directed to methods
for purifying API and perform the same purification steps in the same
order, a person of ordinary skill in the art would have had a reason to
combine the elements because the combination would not change the
principle of operation or the intended functions of the combined
elements. Pet. 18; Ex. 1010 ¶ 24.
For the reasons stated by Petitioner, we are persuaded that
Petitioner has met its burden of showing that a person of ordinary skill
in the art would have had a reason to add the precipitation step of
Coan to Ralston’s method of purifying API with a reasonable
expectation of success. See Pet. 15–18; Ex. 1010 ¶¶ 21–24. In
particular, we are persuaded that adding PEG and adjusting the pH to
precipitate contaminating proteins, as disclosed in Coan, to Ralston is
simply a combination of a well-known technique to yield predictable
results. KSR, 550 U.S. at 416 (“The combination of familiar elements
according to known methods is likely to be obvious when it does no
more than yield predictable results.”).
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In response, Patent Owner argues that a person of ordinary
skill in the art would not be motivated to combine Coan and Ralston
because Ralston allegedly disparages Coan’s use of PEG
precipitation:
Several other groups have combined PEG precipitation
with other purification methods in an attempt to isolate
API. For instance, U.S. Pat. No. 4,379,087, U.S. Pat. No.
4,439,358, U.S. Pat. No. 4,697,003 and U.S. Pat. No.
4,656,254, all employ a PEG precipitation step in
processes of isolating API. PEG precipitation is
disadvantageous in that PEG will also precipitate
hepatitus [sic] B virus. Although viruses are typically
inactivated in a heat pasteurization step following
purification of API, precaution must be taken, and
patients must therefore be immunized before receiving
treatments.
Along with PEG precipitation, U.S. Pat. No.
4,379,087 by Coan et al. also reports a concentration step
involving phosphate buffer and DEAE SEPHAROSETM.
The combined process is quite lengthy, i.e., five days.
Furthermore, the final product is only 60% active and
only 80% pure.
PO Resp. 43–44 (quoting Ex. 1002, 3:45–59). According to Patent
Owner, a skilled artisan reading Ralston would not use Coan’s PEG
precipitation followed by anion chromatography because Ralston
expressly describes it as “disadvantageous.” Id.
We are not persuaded. “A reference may be said to teach away
when a person of ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or would
be led in a direction divergent from the path that was taken by the
applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
Although “known disadvantages in old devices which would naturally
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discourage the search for new inventions may be taken into account in
determining obviousness,” United States v. Adams, 383 U.S. 39, 52
(1966), we are not convinced that Ralston’s description of Coan as
“disadvantageous” would discourage a skilled artisan from modifying
Ralston’s purification method by adding Coan’s PEG precipitation.
Ralston states that PEG precipitation is disadvantageous
because “PEG will also precipitate hepatitis [sic] B virus.” Ex. 1002,
3:50–51. Ralston then states that “[a]lthough viruses are typically
inactivated in a heat pasteurization step following purification of API,
precaution must be taken, and patients must therefore be immunized
before receiving treatments.” Id. at 3:51–54. Both Petitioner and
Patent Owner’s declarants agree, however, that a person of ordinary
skill in the art would have understood in 1999 that virus removal or
viral inactivation was a required step of purifying API. Ex. 2011,
81:24–82:10 (Scandella); Ex. 1034, 75:12–21 (Fournel); Ex. 1032;
105:3–10 (Travis). Thus, we are not persuaded that a skilled artisan,
reading this passage of Ralston, would have been discouraged from
using PEG precipitation, because a skilled artisan would have already
been aware of the need for viral inactivation and the precautions that
should be taken.
Patent Owner also notes that Ralston states that Coan’s
combined process of PEG precipitation along with a concentration
step involving phosphate buffer and DEAE SEPHAROSE is “quite
lengthy” and the “final product is only 60% active and only 80%
pure.” Ex. 1002, 3:55–59. Accordingly, Patent Owner argues that a
person of ordinary skill in the art would be discouraged from
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following the path set out in Coan, would be led in a direction
divergent from the path taken by the applicant, or would not
incorporate Coan’s PEG precipitation step because it would render the
result inoperable. PO Resp. 45–46. We do not find Patent Owner’s
argument persuasive. Ralston does not “criticize, discredit, or
otherwise discourage” the use of Coan’s PEG precipitation along with
Ralston’s purification process with anion and cation exchange resins.
See DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d
1314, 1327 (Fed. Cir. 2009) (quoting In re Fulton, 391 F.3d 1195,
1201 (Fed. Cir. 2004)) (holding that for a reference to teach away, it
must state more than a general preference for an alternative invention,
it must “‘criticize, discredit, or otherwise discourage’ investigation
into the invention claimed.”). Rather, Ralston characterizes Coan’s
“combined process” as lengthy with an 80% pure final product. Ex.
1002, 3:55–59. Thus, although Ralston may teach away from the use
of Coan’s entire process, we are not convinced that a person of
ordinary skill in the art reading Ralston would be discouraged from
using Coan’s PEG precipitation step in light of the benefits discussed
above.
Accordingly, we determine that Petitioner has shown by a
preponderance of the evidence that claims 3, 4, 19, and 20 are
unpatentable as obvious over the combination of Ralston and Coan.
F. Obviousness over Ralston and Hwang
Petitioner asserts that claims 12–15 and 28 are unpatentable as
obvious over Ralston and Hwang alone or in combination with one or
more cited references, relying on the Declarations of Dr. Scandella
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and Bischoff. Pet. 19–23, 25–28; Pet. Reply 10–12; Ex. 1010 ¶¶ 26–
32, 37–46; Ex. 1011 ¶¶ 8–10, 18, 19. Patent Owner disagrees with
Petitioner’s assertions, relying on the Declarations of Dr. Travis and
Mr. Fournel. PO Resp. 46–50; Ex. 2016 ¶¶ 76, 79–82; Ex. 2017
¶¶ 64, 66–69. We incorporate here our earlier findings and discussion
regarding the disclosure of Ralston.
1. Hwang
Hwang relates to a process for purifying API. Ex. 1005, 1:8–
10. In its method, Hwang teaches virus inactivation by solvent-
detergent treatment. Id. at 4:15–16. Specifically, Hwang discloses
using Tween 80 and tri-n-butyl phosphate to inactivate viruses (id. at
2:55–57), and then incubating the solution at pH 8 ± 0.5 to inactivate
any viruses (id. at 4:20–22). Hwang then discloses diluting the treated
solution and applying that solution to an anion exchange medium,
which binds API. Id. at 4:35–40.
2. Analysis
Petitioner asserts that claims 12 and 28 are unpatentable as
obvious over Ralston and Hwang. Pet. 19–23; Pet. Reply 10–11.
Claims 12 and 28 depend from claims 1 and 17, respectively, and
further recite a diluting step before passing the purified solution
through the anion exchange resins. Petitioner asserts that Hwang
teaches the diluting step. Pet. 19–20 (citing Ex. 1005, 4:35–36).
Petitioner also asserts that claim 13 is unpatentable as obvious
over Ralston, Hwang, and Chen. Pet. 25–28; Pet. Reply 12. Claim 13
depends from claim 12 and further requires diluting the purified
solution so that the purified solution has a conductivity of between
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about 2.0 mS and about 6.0 mS. Chen relates to a method of
purifying large quantities of API from fractionated plasma. Ex. 1007,
Abstract. Chen’s method includes adjusting the conductivity of the
Cohn fraction IV-1 suspension to ≤ 5 mmho/cm with NaCl. Id. at
233. Petitioner asserts that Chen teaches this limitation because 5
mmho/cm, as disclosed by Chen, is equivalent to 5 mS/cm and,
therefore, falls within the recited range. Pet. 26; Ex. 1010 ¶ 37.
Finally, Petitioner asserts that claims 14 and 15 are
unpatentable as obvious over Ralston, Hwang, Chen, and Coan II.
Pet. 28–31; Pet. Reply 12. Claims 14 and 15 depend from claims 13
and 14, respectively, and further require that the purified solution is
diluted with water (claim 14) and wherein the water contains sodium
phosphate (claim 15). Coan II relates to purification of API from
Cohn fraction IV-1 by precipitation and ion-exchange
chromatography. Ex. 1008, Abstract. As part of its method, Coan II
teaches dissolving the plasma fraction in one liter of 0.025 M sodium
phosphate. Id. at 2. Petitioner asserts that Coan II teaches the
limitations of claims 14 and 15, given that a one liter solution of 0.025
M sodium phosphate contains 0.025 moles of sodium phosphate
dissolved in approximately one liter of water. Pet. 28–29 (citing
Ex. 1008, 2; Ex. 1010 ¶ 42).
For each of the combinations, Petitioner asserts that one skilled
in the art would have been motivated to include a diluting step in
Ralston’s purification method because it was well known that diluting
a solution containing API changes variables involved in ion exchange,
including the conductivity of the solution. Id. at 21, 26–28, 29–31.
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Accordingly, Petitioner’s declarant concludes that a skilled artisan
who wanted to improve the binding of API to an anion exchange resin
to improve isolation and purification of API would have had a reason
to combine the dilution step of Hwang, Chen, and Coan II with the
purification process of Ralston. Ex. 1010 ¶¶ 29–30; 38–40; 44–46.
In response to each asserted combination, Patent Owner argues
that Ralston teaches away from the use of PEG precipitation. In
particular, Patent Owner focuses on Ralston’s discussion of Japanese
Patent No. 8-99999, which describes using PEG precipitation in
combination with a cation exchanger. Ex. 1002, 3:60–61. According
to Ralston, “[t]he methods described therein do not separate fully
active API from inactive API.” Id. at 3:61–62. Moreover, Ralston
states that “the best yield, achieved by combining PEG precipitation
and SP-cation exchange steps, was only 50%, and does not appear to
be easily scaled up to a commercial production level.” Id. at 3:66–
4:2. Patent Owner concludes that this disclosure amounts to a
discouragement of using PEG precipitation with ion exchange
chromatography. PO Resp. 46–48; Ex. 2016 ¶¶ 76, 80; Ex. 2017
¶¶ 64, 67.
For similar reasons stated above, we are not persuaded that
Ralston’s description of Japanese Patent No. 8-99999 teaches away
from the use of PEG precipitation with the purification method of
Ralston. Specifically, we are not persuaded that Ralston’s disclosure
of the disadvantages of combining PEG precipitation and cation
exchanges steps would discourage a skilled artisan from modifying
Ralston’s purification method by adding PEG precipitation. See
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DePuy Spine, 567 F.3d at 1327. As Patent Owner’s declarant
admitted, Ralston was referring to the entire process being used in that
patent, and not to PEG precipitation alone. Ex. 1032, 150:14–21.
We, therefore, find that Ralston does not discourage the use of PEG
precipitation with its purification method.
Accordingly, we determine that Petitioner has shown by a
preponderance of the evidence that claims 12 and 28 are unpatentable
as obvious over Ralston and Hwang; claim 13 is unpatentable as
obvious over Ralston, Hwang, and Chen; and claims 14 and 15 are
unpatentable as obvious over Ralston, Hwang, Chen, and Coan II.
G. Obviousness over Lebing and Coan
Petitioner asserts that claims 2–5, 12, 16, 18–21, 28, and 32 are
unpatentable as obvious over Lebing and Coan, relying on the
Declarations of Dr. Scandella and Dr. Bischoff. Pet. 31–36; Pet.
Reply 12–15; Ex. 1010 ¶¶ 47–51; Ex. 1011 ¶¶ 10, 18, 19. Patent
Owner disagrees with Petitioner’s assertion, relying on the
Declarations of Dr. Travis and Mr. Fournel. PO Resp. 50–51; Ex.
2016 ¶¶ 67–68, 83; Ex. 2017 ¶¶ 50–52, 70. We incorporate here our
earlier findings and discussion regarding the disclosure of Coan.
1. Lebing
Lebing relates to a method of purifying API from plasma with
flow-through cation exchange chromatography. Ex. 1003, 1:8–10,
2:59–61. The method of the preferred embodiment includes the steps
of dialyzing the protein solution, adjusting the pH of the solution,
passing the solution through a cation exchange chromatography resin,
and collecting the purified API as a flow-through fraction of the
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chromatography. Id. at 2:66–3:9. Lebing also states that for large-
scale productions, “a variety of additional steps, including viral
inactivation may be added to optimize yield, improve viral safety, and
assure regulatory compliance.” Id. at 3:42–45. The additional steps
include:
(1) Initial chromatography on a weak ion exchange resin
(DEAE);
(2) Initial chromatography on a strong anion exchange
resin (QAE);
. . . ; and
(6) Precipitation steps to partially purify starting material
prior to cation chromatography.
Id. at 3:45–58.
2. Analysis
For the reasons stated in the Petition and Dr. Scandella’s
declaration, we determine that the combination of Lebing and Coan
teaches each limitation of dependent claims 2–5, 12, 16, 18–21, 28,
and 32. Pet. 31–33; Ex. 1010 ¶ 47, App’x J, P. For example, Lebing
teaches passing the solution through an anion exchange resin first and
then through a cation exchange resin, as required by independent
claims 1 and 17. See Ex. 1003, 5:32–35 (“In our presently preferred
embodiment, anion exchange chromatography is used to partially
purify the [API] from a Cohn Fraction IV-1 (Fr. IV-1) suspension
before loading onto the strong cation exchange column.”), Fig. 2.
Regarding the initial precipitation step, we find persuasive Petitioner’s
assertion that Coan teaches PEG precipitation as the first step in the
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purification process. Ex. 1010, App’x P (citing Ex. 1004, 4:20–22,
4:56–59).
Petitioner makes similar arguments as above for why a person
of ordinary skill in the art would have had a reason to include Coan’s
PEG precipitation step to remove contaminating proteins and lipids in
the method of Lebing. Pet. 33–36; Ex. 1010 ¶¶ 48–50. For example,
Petitioner asserts that a skilled artisan would have included Coan’s
precipitation step because it was well known that contaminating
proteins may interfere with the ion exchange sites on the resin,
thereby making the resin less available for binding API, which, in
turn, interferes with chromatography. Pet. 34; Ex. 1010 ¶ 48.
Petitioner also argues that it was well known that contaminating
materials may reduce the flow rate of a solution through an ion
exchange column and “foul the column.” Pet. 34–35; Ex. 1010 ¶¶ 48–
49. For the same reasons stated above, we are persuaded that
Petitioner has made a sufficient showing that a skilled artisan would
have had a reason to combine Lebing and Coan.
In response, Patent Owner argues that a person of ordinary skill
in the art would not combine Lebing with Coan because the ’180
patent Specification criticizes the Lebing process as “too resource
intensive for large-scale manufacturing.” PO Resp. 50 (quoting Ex.
1001, 2:46–50). Patent Owner also argues that, according to Ralston,
Lebing’s process tends to occlude the column, requiring larger
columns, additional dialysis/filtration steps, and at least two cation
chromatography steps, which “reduce efficiency and practicality of
the method for large-scale processes.” Ex. 1002, 4:15–26. Because
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Ralston allegedly criticizes both Coan and Lebing, Patent Owner
argues that there is no motivation to combine the two references. PO
Resp. 51 (citing Ex. 2016 ¶ 83; Ex. 2017 ¶ 70). Finally, Patent Owner
asserts that neither Lebing nor Coan teaches or suggests the steps of
the claims in the claimed order. Id. (citing Ex. 2016 ¶ 83; Ex. 2017
¶ 70).
We do not find Patent Owner’s arguments persuasive.
Regarding the order of steps, we have already found that Coan teaches
an initial PEG precipitation step. See Ex. 1004, 4:20–22, 4:56–59.
Moreover, Lebing suggests “[p]recipitation steps to partially purify
starting material prior to cation chromatography.” Ex. 1003, 3:57–58
(emphasis added). Taken together, we agree with Petitioner that the
combination suggests adding Coan’s precipitation step to the
beginning of Lebing’s purification method. Pet. Reply 12–13; see
also Ex. 1032, 109:16–110:9 (Dr. Travis agreeing that the starting
material is a Cohn Fraction IV-1 paste). During oral argument,
counsel for Patent Owner agreed that Lebing suggests the
precipitation step on the starting material is the first step. Tr. 49:20–
24. Counsel disagreed, however, that the precipitation step would
come before both an anion and a cation chromatography step. Rather,
counsel for Patent Owner asserted that the precipitation step would
replace the anion step. Tr. 49:24–50:6. Counsel, however, provided
no evidence in support of this assertion, other than attorney argument.
Because attorney argument is no substitute for evidence, we decline to
give this argument any weight. See Johnston v. IVAC Corp., 885 F.2d
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1574, 1581 (Fed. Cir. 1989) (“Attorneys’ argument is no substitute for
evidence.”).
Moreover, we are not persuaded that Ralston’s statements
regarding Coan and Lebing would discourage a person of ordinary
skill in the art from combining the Coan PEG precipitation step with
the Lebing method. As explained above, we do not consider
Ralston’s statements regarding PEG precipitation as disparaging the
incorporation of a PEG precipitation step into a method like Lebing’s.
See DePuy Spine, 567 F.3d at 1327. Moreover, notwithstanding
Patent Owner’s assertions to the contrary, we find that Ralston’s
statement that Lebing’s initial anion chromatography step binds
numerous contaminating proteins that tend to occlude the column
actually supports the combination. See Ex. 1002, 4:15–22. As
explained above, we are persuaded that a person of ordinary skill in
the art would have had a reason to add the Coan PEG precipitation
step to Lebing’s method to remove the contaminating proteins to
improve yield and purity.
Accordingly, we determine that Petitioner has shown by a
preponderance of the evidence that claims 2–5, 12, 16, 18–21, 28, and
32 are unpatentable as obvious over the combination of Lebing and
Coan.
H. Secondary Considerations of Nonobviousness
Factual inquiries for an obviousness determination include
secondary considerations based on evaluation and crediting of
objective evidence of nonobviousness. See Graham, 383 U.S. at 17.
Notwithstanding what the teachings of the prior art would have
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suggested to one of ordinary skill in the art at the time of the
invention, the totality of the evidence submitted, including objective
evidence of nonobviousness, may lead to a conclusion that the
challenged claims would not have been obvious to one of ordinary
skill in the art. In re Piasecki, 745 F.2d 1468, 1471–72 (Fed. Cir.
1984). Secondary considerations may include long-felt but unmet
needs, failure of others, unexpected results, commercial success,
copying, licensing, and praise. See Graham, 383 U.S. at 17; Leapfrog
Enters., Inc. v. Fisher-Price, Inc., 485 F.3d 1157, 1162 (Fed. Cir.
2007).
To be relevant, evidence of nonobviousness must be
commensurate in scope with the claimed invention. In re Kao, 639
F.3d 1057, 1068 (Fed. Cir. 2011) (citing In re Tiffin, 448 F.2d 791,
792 (CCPA 1971)); In re Hiniker Co., 150 F.3d 1362, 1369 (Fed. Cir.
1998). In that regard, to be accorded substantial weight, there must be
a nexus between the merits of the claimed invention and the evidence
of secondary considerations. In re GPAC Inc., 57 F.3d 1573, 1580
(Fed. Cir. 1995). “Nexus” is a legally and factually sufficient
connection between the objective evidence and the claimed invention,
such that the objective evidence should be considered in determining
nonobviousness. Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
851 F.2d 1387, 1392 (Fed. Cir. 1988). The burden of showing that
there is a nexus lies with the patent owner. Id.; see Paulsen, 30 F.3d
at 1482. Here, Patent Owner argues that longfelt but unmet need, the
failure of others, and the unexpected results of the process claimed in
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the ’180 patent indicates that the claims would not have been obvious
to a person of ordinary skill in the art. PO Resp. 52–59.
1. Longfelt Need and Failure of Others
“Longfelt need is closely related to failure of others. Evidence
is particularly probative of obviousness when it demonstrates that a
demand existed for the patented invention, and that others tried but
failed to satisfy the demand.” In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1082 (Fed.
Cir. 2012).
Here, Patent Owner argues that there was a shortage of API and
a crucial need for “more efficient and production-ready processes.”
PO Resp. 53–54. Patent Owner notes that “the failure of others to
mass produce sufficient amounts of [API] to meet the needs created
by market demand demonstrates the claims of the ’180 patent are not
obvious.” Id. at 55. Patent Owner asserts that this long-felt but unmet
need is the problem that the invention of the ’180 patent solved, as
evidenced by Prolastin®-C, which Patent Owner and its declarants, Dr.
Rebbeor and Mr. Fournel, contend is manufactured using the claimed
invention. PO Resp. 52–53; Ex. 2018 ¶¶14–15; Ex. 2017 ¶¶ 71–77.
According to Mr. Fournel:
Despite efforts throughout the industry, until the ’180
patent no one successfully developed a process that
significantly increased yield, did not compromise purity,
and was efficient enough for large-scale commercial
production. Each proposed method (e.g., Lebing ’285,
Ralston, etc.) presented various disadvantages,
particularly relating to the inability to be scaled up into a
commercial process.
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Ex. 2017 ¶ 73. Patent Owner further asserts that others have
attempted to develop a production-ready purification process for API,
but nothing was commercialized. PO Resp. 56; see also Ex. 2017
¶ 13.
The problem with this argument is that the claims do not
require large-scale commercial production or specific levels of purity
and yield. Regardless, Ralston states:
The present process provides API with a product purity
of >90%; and yield at manufacturing scale of >70%.
Moreover, of all the API collected by the present method,
greater than 90% of it is in its active form. In fact, the
method of the present invention can produce API isolates
having greater than about 95% active API; and can be as
much as 100% active.
Ex. 1002, 4:66–5:5. Thus, to the extent there was a longfelt need for a
an API purification process that resulted in high product purity and
yield, Ralston—at least on its face—appears to have met that need.
Id.
During oral argument, counsel for Patent Owner attempted to
cast doubt on Ralston’s results, stating vaguely that Dr. Travis “has a
reason to disbelieve the claims of Ralston.” Tr. 55:18–20. Counsel
also stated “[t]here is no product on the market that we know about
that actually practices Ralston” and “[t]here is nothing to suggest that
it actually works.” Id. at 55:20–23. But there is any number of
reasons why Ralston (or anyone else) did not commercialize its
process. Patent Owner offers no data of its own, testing Ralston’s
method to support its assertion that Ralston’s claims should be
disbelieved. Without any evidence to the contrary, we decline to
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speculate or question the veracity of Ralston’s disclosure based on
counsel’s offhand remarks during oral argument.
Accordingly, we determine that Patent Owner has not
established a long-felt need or the failure of others.
2. Unexpected Results
Patent Owner argues that the challenged claims are nonobvious
because the order of steps in the production process and the inclusion
of a precipitation step produced API at an unexpected and surprising
level of efficiency and purity beyond that achieved by the prior art.
PO Resp. 57. According to Patent Owner’s declarant, Dr. Rebbeor,
the ’180 inventors found that adding a precipitation step before anion
and cation exchange resins unexpectedly resulted in higher yield,
higher purity, shorter production time, and use of less resources than
previously known methods. Ex. 2018 ¶ 10 (citing data in Ex. 2019).
Dr. Rebbeor states that data shows that Prolastin®-C, the product
made by the methods of the ’180 patent, achieved vast improvements
over Prolastin®, a product made using the best prior art method at the
time, in yield, purity, cycle time, and significantly reduced labor
hours, machine hours, and the total cost of production. Ex. 2018 ¶ 18;
Ex. 2019, 1. Dr. Travis explains that the increase in both yield and
purity is unexpected because a person of ordinary skill in the art
would expect that an increase in yield would result in a decrease in
purity, and vice versa. Ex. 2016 ¶ 87.
In response, Petitioner notes that the ’180 patent does not
contain any data to support its claim of unexpected results. Pet. Reply
16. Petitioner then criticizes Patent Owner’s reliance on newly
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generated data from 2014 to show the claimed process yielded
unexpected results, asserting that doing so is contrary to the law. Id.
(citing Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 769 F.3d
1339, 1340–41 (Fed. Cir. 2014) (per curiam) (Dyk, J., concurring)
(“This case presents a question of obviousness, in particular whether
evidence postdating the invention can be used to establish unexpected
results. The panel holds that it cannot be considered in the
circumstances of this case.”)).
Petitioner also argues that Patent Owner fails to account for the
unclaimed steps in the Prolastin®-C process, and the differences
between the process for Prolastin® (i.e., the “Hein process”) and for
Prolastin®-C. Pet. Reply 17.
We find Petitioner’s arguments more persuasive. First, we are
persuaded that the Prolastin®-C data produced in 2014 does not reflect
the results that would have been expected (or unexpected) at the time
of the invention in 1999. “To be particularly probative, evidence of
unexpected results must establish that there is a difference between
the results obtained and those of the closest prior art, and that the
difference would not have been expected by one of ordinary skill in
the art at the time of the invention.” Bristol-Myers Squibb Co. v. Teva
Pharm. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (emphasis
added); see also Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
769 F.3d 1339, 1341 (Fed. Cir. 2014) (Dyk, J., concurring in denial of
petition for rehearing en banc) (stating under the circumstances of the
case that the “decision properly does not allow consideration of post-
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invention evidence” regarding unexpected results). Accordingly, we
give the 2014 Prolastin®-C data little weight in our analysis.
Moreover, even if we did consider the 2014 data, we are
persuaded that Patent Owner has not met its burden of establishing a
nexus between a novel feature of the claimed invention and the
unexpected results. For example, Patent Owner has not accounted for
the additional unclaimed steps in the Prolastin®-C method, like the
dissolution step, which Patent Owner’s declarants admit affect purity
and yield. Ex. 1033, 46:3–21 (stating the step of dissolving Cohn
Fraction IV-1 “is important with respect to yield”); Ex. 1034, 68:4–
11. Furthermore, the Hein process for Prolastin® uses heat
pasteurization, which negatively affects API yield. Ex. 2017 ¶ 72.
Thus, because the Prolastin®-C method does not include the heat
pasteurization step, that would explain, at least in part, the higher
yield of Prolastin®-C. Pet. Reply 18.
Given these issues with Patent Owner’s argument, we
determine that Patent Owner has not offered sufficient evidence to
establish unexpected results.
I. Conclusion
Having considered Petitioner’s prima facie case of obviousness
and Patent Owner’s arguments and evidence in rebuttal, we evaluate
all of the evidence together to make a final determination of
obviousness. In re Eli Lilly &Co., 902 F.2d 943, 945 (Fed. Cir. 1990)
(“After a prima facie case of obviousness has been made and rebuttal
evidence submitted, all the evidence must be considered anew.”). In
doing so, we conclude that Petitioner has shown by a preponderance
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of the evidence that each of the challenged claims is unpatentable as
obvious over the cited references.
PATENT OWNER’S MOTION TO EXCLUDE EVIDENCE III.
Patent Owner filed a motion to exclude evidence offered by the
Petitioner. The party moving to exclude evidence bears the burden of
proving that it is entitled to the relief requested—namely, that the
material sought to be excluded is inadmissible under the Federal Rules
of Evidence (“FRE”). See 37 C.F.R. §§ 42.20(c), 42.62(a).
Patent Owner moves to exclude portions of Petitioner’s Reply
to Patent Owner’s Response as newly raised material that was not in
the Petition, is not part of the grounds in the Decision to Institute, and
is outside the scope of Patent Owner’s Response. Specifically, Patent
Owner moves to exclude Petitioner’s argument regarding Ralston’s
disclosure of purifying the milk of transgenic animals, and the
testimony of Dr. Travis and Exhibits 1035–1036, which are related to
that argument. Paper 34, 1–2, 7–10. While we agree that that
argument is newly raised in the Reply, we did not rely on that
argument or any related testimony or exhibits for purposes of this
Decision. Patent Owner’s arguments are, therefore, moot.
Patent Owner also seeks to exclude Exhibits 1022 and 1026,
which are documents created during the deposition of Dr. Travis, and
any testimony regarding those exhibits. Id. at 3–5. We did not rely
on Exhibits 1022 or 1025 or the related testimony for purposes of this
Decision. Patent Owner’s arguments are, therefore, moot.
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Because we did not consider any of the evidence that Patent
Owner moves to exclude for purposes of this Decision, Patent
Owner’s motion is dismissed as moot.
CONCLUSION IV.
We conclude that Petitioner has shown by a preponderance of
the evidence that claims 1–5, 10–21, 26–28, 32, and 33 of the ’180
patent are unpatentable.
ORDER V.
In consideration of the foregoing, it is hereby:
ORDERED that claims 1–5, 10–21, 26–28, 32, and 33 of the
’180 patent are held unpatentable;
FURTHER ORDERED that Patent Owner’s Motion to Exclude
Evidence is dismissed as moot; and
FURTHER ORDERED that, because this is a Final Written
Decision, the parties to the proceeding seeking judicial review of the
decision must comply with the notice and service requirements of 37
C.F.R. § 90.2.

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PETITIONER:

Sanjay K. Murthy
Christopher J. Betti
K&L GATES LLP
sanjay.murthy@klgates.com
christopher.betti@klgates.com

PATENT OWNER:

Barry Herman
Carl Massey
Preston Heard
Bernard Brown
WOMBLE CARLYLE SANDRIDGE & RICE LLP
bherman@wcsr.com
cmassey@wcsr.com
pheard@wcsr.com
bebrown@wcsr.com